Two new series of the indole-based sulfonamide derivatives were synthesized by the reaction of various sulfonylhydrazides with N-substituted indole 3-carboxaldehydes (4a-j). Crystallographic parameters and intramolecular interactions of compound HS4 were examined through x-ray crystallography to establish the structure of compound. The biological activity of the synthesized compounds was evaluated against breast cancer cell line 4T1 and rat adipose-derived stem cells (rADSC). Among all the compounds, HS3 and MP3 possessed significant antiproliferative activity against 4T1 malignant cells inhibiting the cell growth with IC50 values of 25 and 37.5 mu M, respectively. Compounds HS3 and MP3 were toxic to rADSCs at 25 and 37.5 mu M concentration, respectively. Further mechanistic studies revealed that compounds HS3 and MP3 induced effective autophagy to cause cell death, confirmed by the progressive conversion of LC3I to LC3II and enhanced expression of LC3A/B in 4T1 breast cancer cells. In addition, the in silico physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling validated the drug likeness properties of the synthesized compounds.

To combat resistant bacterial strains, a series of compounds (8a-8n) were synthesized in moderate to excellent yields (32.8-94.0%). These analogs were subjected to preliminary screening against various bacterial strains, including Enterococcus faecalis, Escherichia coli, Bacillus subtills, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, to evaluate their effectiveness as antibacterial agents. Compounds 8f and 8i were the most effective derivatives, displaying their best antibacterial activity against K. pneumoniae with MIC values of 16 and 32 µg/mL, respectively. Additionally, compound 8f demonstrated a beneficial synergistic effect with ampicillin. The compound 8f was found to show good interactions with dihydropteroate synthase via hydrogen bonding, π-cation interaction and π-π stacking interactions. The binding free energy (BFE) value was calculated to be -63.91 Kcal/mol. The molecular dynamics simulation showed low RMSD values (0.6 to 2.2 Å) of DHPS-8f complex and apoprotein, suggesting a stronger binding affinity. Importantly, it exhibited no toxicity toward human red blood cells (hRBC). Furthermore, the absorption, distribution, metabolism, and excretion (ADME) profile of 8f indicated its favorable drug-like characteristics.

Antibiotic-resistant bacteria are a serious global health threat, making infections harder to treat and increasing medical costs and mortality rates. To combat resistant bacterial strains, a series of compounds (QS1-12) were synthesized with an excellent yield of 85-92%. Initial assessments of these analogues as potential antibacterial agents were conducted through a preliminary screening against a panel of diverse bacterial strains. The results identified compound QS-3 as the most effective antibacterial candidate, exhibiting exceptional inhibitory activity against P. aeruginosa with a minimum inhibitory concentration (MIC) of 64 μg mL-1. Furthermore, QS-3 demonstrated a favorable synergistic effect when combined with ciprofloxacin. Notably, the compound displayed minimal cytotoxicity, inducing less than 5% lysis of red blood cells (RBCs). Significantly, QS-3 exhibited enhanced inhibitory activity, particularly against the antibiotic-resistant strains AA202 and AA290. In silico predictions of physicochemical properties underscored the drug-like qualities of the designed compounds. Additionally, molecular docking poses, ligPlot images, and a binding affinity of -8.0 kcal mol-1 further reinforced their potential as promising antibacterial agents. Briefly, the reported compound QS3 may be a future broad-range antibacterial agent.

In an unremitting search for potential antiprotozoal agents, a series of 2-(3-((2-(2-(quinolin-4-yloxy)acetyl)hydrazineylidene)methyl)-1H-indol-1-yl)acetamide derivatives (QC1-QC11) was designed, synthesized, characterized and evaluated for its antiprotozoal activities. The anti-amoebic activity of these synthesized compounds was assessed against the HM1:IMSS strain of Entamoeba histolytica. All the compounds exhibited good to potent activity with IC50 values in the range of 0.36-30.94 µM and metronidazole (MTZ) was taken as standard (IC50 = 1.8 µM). Compound QC4 was recorded with lowest IC50 value (0.36 µM). Antimalarial screening against Plasmodium falciparum strain (NF54) revealed the poor efficacy of these compounds. Derivatives QC2 and QC4 exhibited a slight inhibitory effect on the malaria parasite compared to quinine, while showing negligible impact on red blood cell integrity. Of all the derivatives, QC4 displayed general toxicity to all the organisms and cells used in this study, with QC2 showing minimal toxicity to these biological systems. The docking study of these derivatives indicated the promising binding affinity when interacted with enzyme EhTHRase (PDB id: 3D8X). QC6 recorded with most negative binding free energy value (-8.9 kcal/mol) showing strongest interaction while QC4 also had promising interaction with binding free energy -8.7 kcal/mol, hence, these derivatives are found to be promising anti-amoebic agents.

In this investigation, we synthesized substituted 1,2,4-oxadiazole-sulfonamide conjugates (8 a-8 l) through a multistep synthetic approach. These compounds were then evaluated against six bacterial strains, consisting of three Gram-positive and three Gram-negative strains. Among them, compound 8 d displayed notable inhibitory activity, with minimum inhibitory concentration (MIC) values of 64 mu g/mL observed against the Gram-positive bacteria Staphylococcus aureus and Enterococcus faecalis. Notably, in the disk diffusion assay, compound 8 d exhibited the most substantial zone of inhibition (ZOI) against Escherichia coli and S. aureus, with respective ZOI measurements of 14 mm and 15 mm, both at a concentration of 2MIC. Additionally, supplementary investigations, including the Fractional Inhibitory Concentration Index (FICI) provided further support for the inhibitory potential of 8 d against the standard bacterial strains. When combined with Ampicillin (Amp), it demonstrated a synergistic effect, significantly augmenting its antibacterial activity against Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis. Importantly, it exhibited no toxicity toward human red blood cells (hRBC). Furthermore, The Absorption, Distribution, Metabolism, and Excretion (ADME) profile of 8 d indicated its favorable drug-like characteristics. A series of novel I,2,4-oxadiazole sulfonamides were synthesized, characterized, and tested for antimicrobial activity. Compound 8 d emerged as the most potent one on which further antimicrobial studies were performed. Notably this compound demonstrated good antimicrobial activity against both the tested gram positive and negative bacterial strains.image

To discover novel carbonic anhydrase (CA, EC 4.2.1.1) inhibitors for cancer treatment, a series of 4-{4-[(hydroxyimino)methyl]piperazin-1-yl}benzenesulfonamides were designed and synthesized using SLC-0111 as the lead molecule. The developed novel compounds 27-34 were investigated for the inhibition of human (h) isoforms hCA I, hCA II, hCA IX, and hCA XII. The hCA I was inhibited by compound 29 with a Ki value of 3.0 nM, whereas hCA II was inhibited by compound 32 with a Ki value of 4.4 nM. The tumor-associated hCA IX isoform was inhibited by compound 30 effectively with an Ki value of 43 nM, whereas the activity of another cancer-related isoform, hCA XII, was significantly inhibited by 29 and 31 with a Ki value of 5 nM. Molecular modeling showed that drug molecule 30 participates in significant hydrophobic and hydrogen bond interactions with the active site of the investigated hCAs and binds to zinc through the deprotonated sulfonamide group.

A series of novel indole based sulfonohydrazide derivatives (5a-k) containing morpholine heterocyclic ring were synthesized through multistep chemical reactions. The target compounds (5a-k) were prepared by the reaction of substituted phenyl sulfonylhydrazides (2a-k) with morpholine derivative of indole 3-carboxaldehyde. All the target compounds were screened for their anticancer activity in vitro against the estrogen receptor-positive breast cancer line MCF-7 and triple-negative breast cancer cell line, MDA-MB-468. It was found that among all the evaluated compounds, the chemotype 4-chloro-N'-((1-(2-morpholinoethyl)-1H-indol-3-yl)methylene)benzenesulfonohydrazide (5f) showed promising inhibition of both MCF-7 and MDA-MB-468 cancer cells with the respective IC50 values of 13.2 μM and 8.2 μM. Compound 5f was found to be nontoxic against HEK 293 noncancerous cells in the studied concentration range, therefore indicating that such chemotypes inhibit the proliferation of cancerous cells selectively and significantly.

Human African and American trypanosomiasis are the vector-borne parasitic diseases that have killed millions of people early, and many people are yet suffering from these neglected diseases. The causative agents of these infections are parasitic protozoans of the genus Trypanosoma. Current treatment regimens against these endemic diseases have several limitations in terms of safety, efficacy, route of administration, and some of them have lost efficacy due to the emergence of resistance in their respective parasites. In this review, the most promising compounds identified by different strategies of drug development against these neglected diseases including target-based approach, the phenotypic high-throughput screening, the drug repurposing approach and combination therapy are emphasized. The potent heterocyclic compounds currently undergoing pre-clinical or clinical studies have also been assessed to ascertain an effective class of organic compounds having significant therapeutic potential against these tropical diseases. The molecular hybridization of outlined motifs may result in more active compounds and circumvent the development of resistance by specific targets in future.

A series of hybrid molecules bearing 5-nitroimidazole linked with substituted piperazine molecules have been synthesized. The cytotoxicity of all the synthesized compounds has been evaluated on HEK293 cells with the help of MTT assay. It was found that the treatment of these compounds shows a variable toxicity profile for HEK293 cells. The results of cytotoxicity showed that in the tested concentration range, compound NJ3, NJ5, NJ8 and NJ10 show considerable cytotoxicity towards HEK293 cells.

Heterocyclic scaffolds are widely utilized for drug design by taking into account the molecular structure of therapeutic targets that are related to a broad spectrum of ailments, including tumors. Such compounds display various covalent and non-covalent interactions with the specific residues of the target proteins while causing their inhibition. There is a substantial number of heterocyclic compounds approved for cancer treatment, and these compounds function by interacting with different therapeutic targets involved in tumorogenesis. In this review, we trace and emphasize the privileged heterocyclic pharmacophores that have immense potency against several essential chemotherapeutic tumor targets: microtubules, kinases and carbonic anhydrases. Potent compounds currently undergoing pre-clinical and clinical studies have also been assessed for ascertaining the effective class of chemical scaffolds that have significant therapeutic potential against multiple malignancies. In addition, we also describe briefly the role of heterocyclic compounds in various chemotherapy regimens. The optimized molecular hybridization of delineated motifs may result in the discovery of more active anticancer therapeutics and circumvent the development of resistance by specific targets in the future.

In this work, substituted 1,2,4-oxadiazoles (OX1-OX27) were screened against five bacterial strains, identified to be OX7 and OX11 as growth inhibitors with minimum inhibitory concentration (MIC) values of 31.25 and 15.75 μg/mL, respectively. The growth inhibitory property of OX7 and OX11 was further validated by disk diffusion, growth curve, and time kill curve assays. Both disrupted biofilm formation with 92-100% reduction examined by the XTT assay were further visualized by scanning electron microscopy analysis. These compounds in combination with ciprofloxacin also exhibit synergy against Escherichia coli cells. With insignificant cytotoxic behavior on HEK293 cells, human red blood cells, and Galleria mellonella larvae, OX11 was tested against 28 multidrug resistant environmental isolates of bacteria and showed inhibition of Kluyvera georgiana and Citrobacter werkmanii strains with 32 and 16 μg/mL MIC values, respectively. The synergistic behavior of OX11 with ampicillin showed many fold reductions in MIC values against K. georgiana and Klebsiella pneumoniae multidrug resistant strains. Further, transmission electron microscopy analysis of OX11-treated E. coli cells showed a significantly damaged cell wall, which resulted in the loss of integrity and cytosolic oozing. OX11 showed significant changes in the secondary structure of human serum albumin (HSA) in the presence of OX11, enhancing HSA stability. Overall, the study provided a suitable core for further synthetic alterations and development as an antibacterial agent.

Metronidazole and its derivatives are widely used for the treatment of amoebiasis. However, metronidazole is considered as the standard drug but it has many side effects. The present study describes the synthesis of a series of metronidazole based thiazolidinone analogs via Knoevenagel condensation of 4-[2-(2-methyl-5-nitro-1H-imidazole-1-yl)ethoxy]benzaldehyde 1 with various thiazolidinone derivatives 2-14 to get the new scaffold (15-27) having better activity and lesser toxicity. Six compounds have shown better efficacy and lesser cytotoxicity than the standard drug metronidazole towards HM1: IMSS strain of Entamoeba histolytica. These compounds may combat the problem of drug resistance and might be effective in identifying potential alternatives for future drug discovery against EhOASS.

All around the world, the percentage of deaths due to cancer is continuously increasing-the greatest devastation of deaths. Among all medications, Unani medicines are boon for human beings to treat cancer with no or least side effects. About 80% rural population use natural products for primary health care. Cuscuta reflexa Roxb. (family Cuscutaceae) is utilized in traditional medicines for curing cancer and other diseases, and it is considered as the most significant plant in the Unani medicinal system. The extracts of Cuscuta reflexa Roxb. were obtained to measure the anticancer activity with H-1299 and MCF-7 cancer cell lines. Soxhlet extraction was utilized for stem and seeds. The anticancer activity of fractions of each extract obtained by using Flash chromatography was also checked. Besides, the antioxidant activity of each fraction was also checked. DNA binding study supported the results obtained during whole process. The cellular death was detected utilizing ELISA. The results indicated that extracts of Cuscuta reflexa Roxb. exhibited strong anticancer activities as compared to the fractions of each extract. Cuscuta reflexa Roxb. extracts indicated noteworthy cytotoxicity against human H-1299 and (lung cancer) MCF-7 cancer cells (breast cancer). The extract of this plant may be given to the patients having lung cancer and breast cancer.

Microtubule affinity regulating kinase 4 (MARK4) is a Ser/Thr kinase, considered as a potential drug target for cancer, diabetes and neurodegenerative diseases. Due to its significant role in the development and progression of cancer, different in-house libraries of synthesized small molecules were screened to identify potential MARK4 inhibitors. A small library of hydrazone compounds showed a considerable binding affinity to MARK4. The selected compounds were further scrutinized using an enzyme inhibition assay and finally two hydrazone derivatives (H4 and H19) were selected that show excellent inhibition (nM range). These compounds have a strong binding affinity for MARK4 and moderate binding with human serum albumin. Anticancer studies were performed on MCF-7 and A549 cells, suggesting H4 and H19 selectively inhibit the growth of cancer cells. The IC50 value of compound H4 and H19 was found to be 27.39 μM and 34.37 μM for MCF-7 cells, while for A549 cells it was 45.24 μM and 61.50 μM, respectively. These compounds inhibited the colonogenic potential of cancer cells and induced apoptosis. Overall findings reflect that hydrazones/hydrazone derivatives could be exploited as potential lead molecules for developing effective anticancer therapies via targeting MARK4.

Microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase involved in the phosphorylation of MAP proteins that regulates microtubule dynamics and abets tumor progression by participating in oncogenic signaling pathways. It is overexpressed in multiple human malignancies and no drug is available for this potential therapeutic target at present. Therefore, using the structure based drug design strategy, a library of hydroxylamine derivatives of morpholine were designed and synthesized as small molecule inhibitors of MARK4. Compound32having the CF(3)group at theorthoposition of the phenyl ring tethered with the >C=NOH core and the hinge binder morpholine component was found to be a potent and selective inhibitor of MARK4 over thirty other serine-threonine kinases. Study of cell viability and compound induced morphological changes in MCF-7 cancer cells discovered that molecule32caused death of cancerous cells through the mechanism of apoptosis. Compound32may be transported and delivered to the target site through the blood stream, and has promising antioxidant potential. Such bio-active molecules could serve as optimized lead candidates in drug discovery for cancer treatment through MARK4 inhibition.

Microtubule affinity-regulating kinase 4 (MARK4), a member of the serine/threonine kinase family, is an emerging therapeutic target in anticancer drug discovery paradigm due to its involvement in regulation of microtubule dynamics, cell cycle regulation, and cancer progression. Therefore, to identify the novel chemical architecture for the design and development of novel MARK4 inhibitors with concomitant radical scavenging property, a series of small-molecule arylaldoxime/5-nitroimidazole conjugates were designed and synthesized via multistep chemical reactions following the pharmacophoric hybridization approach. Compound 4h was identified as a promising MARK4 inhibitor with high selectivity toward MARK4 inhibition as compared to the panel of screened 30 kinases pertaining to the serine/threonine family, which was validated by molecular docking and fluorescence binding studies. The comprehensive cell-based examination divulged the promising apoptotic, antiproliferative, and antioxidant potential for the chemotype 4h. The compound 4h was endowed with the K a value of 3.6 × 103 M-1 for human serum albumin, which reflects its remarkable transportation and delivery properties to the target site via blood. The present study impedes that in the future, such compounds may stand as optimized pharmacological lead candidates in drug discovery for targeting cancer via MARK4 inhibition with a remarkable anticancer profile.

Isoxazole-triazole conjugates (8a-q) were synthesized using click chemistry approach and their biological activities were explored to develop novel antibacterial agents. In vitro antibacterial screening against Gram-positive as well as Gram-negative bacterial strains identified compounds 8b and 8m with potent inhibitory potential against selective bacterial cells. 8b showed IC50 value of 67.6 mu g/mL against P. aeruginosa while 8m exhibited better activity against Gram-positive bacteria S. pneumoniae and E. faecalis having IC50 values 74.13 and 44.7 mu g/mL, respectively. Effect on growth kinetics of the bacterial cells as well as cytotoxicity studies on human embryonic kidney cells (HEK293) further supports their biological potential. Compound 8m significantly inhibited biofilm formation of E. coli cells visualized by scanning electron microscopy (SEM) analysis. The interaction of these compounds with ctDNA, as their possible mode of action, was studied using multi-spectroscopic techniques and molecular docking. The data suggested that compound 8m intercalate in the minor groove of DNA. (C) 2019 Elsevier B.V. All rights reserved.

Breast cancer is most frequently detected and leading cause of cancer death in women worldwide. 80% of the breast cancer are estrogen receptor positive and the presently available drugs are ineffective either due to intrinsic resistance or due to acquired resistance. Sulfonamide compounds are a class of compounds showing activities like, antibacterial, antiviral including antitumor. In the present study we have investigated the anti-cancerous activity of sulfonamide derivative CID-6861424 on breast cancer cell line, MCF-7 . Our data shows inhibition of MCF-7 cell viability by CID-6861424 in a concentration and time dependent manner. 50μM was the IC 50 value of CID-6861424 on MCF-7 cell. The compound downregulated cyclin D1 and CDK 4/6, induced G 1 phase cell cycle arrest and apoptotic cell death. 50μM CID-6861424 upregulated ROS generation, disrupted mitochondrial membrane potential (Δ ψm ), increased DNA damage and upregulated tumor suppressor protein, p53 in MCF-7 cells. The compound reduced phosphorylation of Akt and GSK-3β, downregulated Bcl-2 and upregulated Bax indicating apoptotic cell death. These results suggest CID-6861424 as a potential anticancer agent against breast cancer. Keywords: CID-6861424 ; MCF-7 cell, cell cycle, double-strand DNA break, apoptosis. Cite this Article Sumit Kumar Gautam, Afreen Inam, Amir Azam, Neelima Mondal. Induction of G1 phase cell cycle arrest and apoptosis in breast cancer MCF-7 cells by sulphonamide derivative CID-6861424. Research & Reviews: A Journal of Toxicology . 2019; 9(2): 1–19p.

Metastatic prostate cancer, with no effective treatment, is among the leading causes of cancer-associated deaths in men. Overexpression of p38αMAPK has been observed in neuroendocrine prostate cancer patients and in both DU145 and PC-3 cell lines and represents a good drug target. Sulfonamide derivatives have shown biological activities against many human diseases, including cancer. CID-6033590, a sulfonylhydrazide compound, screened from PubChem database by molecular docking with p38αMAPK, was evaluated for anti-cancerous activities. CID-6033590 induced toxicity in both DU145 and PC-3 cells in a concentration and time-dependent manner with an IC50 value of 60 μM and 66 μM, respectively. Sub-cytotoxic concentrations of the compound significantly induced S-phase cell cycle arrest, inhibited cyclinA/CDK2 complex and blocked cell proliferation. Further, CID-6033590 downregulated phosphorylation of p38MAPK (P-p38) as well as its downstream targets, Activating transcription factor 2 (ATF-2) and Heat shock protein 27 (Hsp27). The compound increased ROS and decreased mitochondrial membrane potential (Δψm), downregulated Bcl-2 and survivin and cleaved poly ADP ribose polymerase (PARP) and caspase-3, indicating the induction of apoptosis. The evaluaion of the compound on noncancerous, human prostatic epithelial cell line RWPE-1, and healthy murine tissues yielded no significant toxicity. Taken together, we suggest CID-6033590 as a potential candidate for prostate cancer therapy.

A series of pyrazolines and metal complexes of 3-(furyl)-2-pyrazoline were design, synthesized and their structures were provided by FT-IR, 1 H-NMR, 13 C-NMR, ESI-MS and elemental analysis.These compounds were assessed for their in-vitro anti-amoebic activity against HMI:IMSS strain of Entamoeba histolytica and compared with standard drug metronidazole.Pyrazolines showed better activity in comparison to its mannich base, but the activity of metal complexes is much more promising than pyrazolines.The docking and ADMET studies were also conducted to investigate the probable mode of action.From the docking studies, it showed that E. histolytica thioredoxin reductase protein showed an active site for binding affinity.